There is growing recognition that Alzheimer's Disease (AD) involves more than the aggregation of amyloid-? proteins and hyperphosphorylation of tau protein, as individuals have been identified with these abnormalities yet without clinical evidence of AD. This supplement hypothesizes that excessive glial reactivity, with resulting production of inflammatory mediators, critically disrupts hippocampal microcircuit dynamics via neuronal death and synaptic pruning, and thus leads to impaired memory. We propose to use RNAseq in a murine model of AD to identify candidate glial genes that predict abnormal microcircuit dynamics, thereby generating specific pathophysiological and therapeutic hypotheses. It is likely that multiple genes will be identified and therefore we will also develop a Drosophila pipeline to directly test those hypotheses as well as other candidate molecules in a high-throughput AD system. These studies combine the expertise of two neuroscientists who study hippocampal microcircuits in epilepsy, two neuroimmunologists who study microglia and astrocytes in the murine model of multiple sclerosis, and a neuroscientist who studies glial function in the Drosophila nervous system. Although this team of scientists has not previously worked on AD, they provide a fresh perspective of AD that is well grounded in their area of expertise. The hypothesis also fits well with the overall theme of the parent COBRE grant in Immunology and Infectious Diseases, whose faculty are examining various aspects of innate immunity, which is highly relevant to AD.